Curing type I diabetes would require either the regeneration or the replacement of insulin-producing cells. Islet transplantation has been extensively investigated as a treatment, but the shortage of human donor sources and the low efficiency of islet isolation has largely hampered this therapy. Alternative sources of islets would be desirable. One major focus of study has been the ex vivo cultivation, expansion and differentiation of functional human endocrine cells for clinical applications.
Stem cells offer great potential for cell-replacement therapy. Mouse embryonic stem cells injected into rat striatum were shown to mature into dopaminergic neurones leading to partial recovery in a rat model of Parkinson's disease. Haematopoietic stem cells that regenerate blood cells after bone marrow transplantation are in wide clinical use such as in the treatment of leukemia. Recently, the prospects for using adult stem cells in medical treatments were heightened by Canadian cardiac surgeons, who reported that injecting bone-marrow cells into the heart can boost its function.
Advances in defining the molecular basis of early pancreogenesis have contributed to an understanding of the process of regeneration that occurs in animal models of pancreatic injury and diabetes. However, pancreatic progenitor cell populations remain poorly defined and the subject of considerable debate. The identity of the islet progenitor cells has remained elusive. Identification of the markers that aid the isolation and purification of islet progenitor cell therefore is important to developing regenerated beta-cells in culture for subsequent transplantation into diabetic patients.
Eph receptors, the largest subfamily of receptor tyrosine kinases (RTKs), are important mediators of cell-cell communication regulating cell attachment, shape, and mobility. Eph signaling is crucial for the development of many developmental processes, including embryo patterning, angiogenesis and axon guidance. Emerging evidence also supports a role for these molecules in the formation of adult tissues and organs, such as the nervous and cardiovascular systems.
Both Ephs and ephrins are membrane-bounded and their interaction at sites of cell-cell contact initiate unique bi-directional signaling cascades. Recent studies showed that signaling by Eph receptors controls oocyte maturation in C. elegans by inhibition of MAPK activation demonstrated that EphrinB1 forward and reverse signaling are required during mouse development. Conditional deletion of EphrinB1 revealed that EphrinB1 acts autonomously in neural crest cells and controls their migration. A mutation study in the PDZ binding domain indicated that EphrinB1-induced reverse signaling is required in neural crest cell-derived tissue formation. Those results showed that EphrinB1 acts both as a ligand and as a receptor in a tissue-specific manner during embryognesis.
Combinatorial expression of Eph and Ephrins may define migration and positioning in a wide spectrum of adult tissues. In the small intestine, β-catenin and TCF couple proliferation and differentiation to the sorting of cell populations through controlling the expression the EphB/EphrinB proteins. Eph proteins serve as cell surface markers for monitoring the cell proliferation and differentiation. In vasculogenesis, arteries and veins are morphologically, functionally and molecularly very different. Notch-gridlock(grl) signaling pathway play important role in the development of arteries and veins. Inhibition of grl expression, by gene mutation or antisense RNA, ablates regions of the artery, and expands contiguous regions of the vein, proceed by an increase in expression of the venous marker EphB4 receptor and diminution of expression of the arterial marker EphrinB2.
The findings mentioned above show that Eph widely exists in different epithelial tissues of different species. In an adult animal colon model, Eph expresses only in the proliferating and developing stages of the epithelial cells during normal tissue self renewal, not in stem cells nor in mature cells. Eph also does not express in mesenchymal cells.